The problem of the administration of taxanes (paclitaxel or docetaxel), camptothecin and derivatives thereof, etoposide and poorly water-soluble antiviral compounds (such as acyclovir), has still to be satisfactorily solved notwithstanding the many efforts described in literature. All the drugs mentioned above induce serious side effects in the patients, e.g. peripheral neuropathies, bradicardia, toxicity on mucus membranes and venous system.
By way of example, paclitaxel is at present formulated at a concentration of 2 mg/ml with the castor oil polyethoxylated derivative Cremophor EL®, containing 50% ethanol. The preparation is administered by injection. A serious hypersensitivity to paclitaxel is usually related to Cremophor EL®, used for its administration. As a consequence, the patients receive a pre-treatment either orally with Desametasone or intravenously with Diphenhydramine and Ranitidine before administration of Paclitaxel, to reduce the risk of hypersensitivity. This pre-treatment and the connected risks for the patient would not be necessary avoiding the use of Cremophor®. Moreover, the cost of paclitaxel treatment would be significantly lowered.
Many efforts to improve the administration of taxanes to patients are being described in literature, but to date none of them has apparently provided definitive improvements. Among said efforts, the following can be mentioned:                Nanospheres of block copolymers loaded with paclitaxel, e.g. biodegradable compounds of methoxy-PEG-polycaprolacton (S. Yeon Kim, et al. Biomaterials 22 (2001 1697-1704) or methoxy-PEG-polylactic-co-glycolic (PLGA) (Ji-Heung Kim et al. Polymers for advanced technologies, 10 649, 1999) or hydrophobized poly(L-lysine citramide imide) (M. Veil et al. Journal of Bioactive and compatible polymers, Vol. 15 No. 2, 99-114 (2000).        Polymers conjugated with such water-soluble polymers as polyglutamic acid, polyaspartic acid or polylisine (U.S. Pat. No. 6,441,025), or prodrugs conjugated with polyethylene glycol derivatives.        Inclusion complexes of paclitaxel with cyclodextrins. Cyclodextrins are cyclic oligosaccharides with 6-8 glycosidic units linked by an α-1-4 bond and characterized by a hydrophobic cavity in their structures, able to solubilize water-insoluble drugs. By way of example, 2-6-dimethyl-β-cyclodextrin is known as it forms inclusion compounds with paclitaxel, with solubility of 2.3 mmoles/l (about 3 g/l) (H. Hamahada et al., Journal of Bioscience and Bioengineering, 2006, 102, 369-371). The main drawback of inclusion complexes of taxanes with modified cyclodextrins is their poor solubility in aqueous media. In practice, the formation of complexes by mixing paclitaxel solutions in water-soluble solvents, e.g. alcohols, with aqueous solutions of cyclodextrin derivatives is at first apparently promising. However, the resulting clear solutions in time release again insoluble paclitaxel, which is subtracted from the complex as it crystallizes separately. Freeze-drying of the paclitaxel solution followed by redissolution of the residue in water also fails, as even in this case paclitaxel crystallizes off. This problem is solved only to some extent using cyclodextrin dimers. Furthermore, the individual cyclodextrins are mutually linked in these dimers by amino bridges, giving the molecule some toxicity.        Cyclodextrin straight polymers in which cyclodextrin groups have random distribution along the polymeric chain. These polymers suffer, in the formation of complexes with paclitaxel or similar drugs, from the same restrictions as free cyclodextrins, as cooperation of the different cyclodextrin units present in the polymer is hindered in that they are distributed along the polymeric chain and thus distant when the polymer in solution acquires a comparatively distended conformation.        
As regards camptothecin, to overcome its stability (opening of the lactone ring to the carboxylate form) and solubility problems several approaches have been investigated. In particular, the complexation with α-cyclodextrins increases the stability of captothecin, thus ameliorating the solubility and cytotoxicity profile (Kang et al. Eur. J. Pharm. Biopharm. 2002, 15, 163-170).
Acyclovir has short half-life (about 2 h) and its absorption is not complete (bioavailability about 15-30%). Due to its limited oral bioavailability Acyclovir must be taken orally five times a day (200 mg every 4 h), while intravenous formulations (5 mg/kg) must be administered every 8 hours for at least 5 days. Moreover, the intravenous dose of Acyclovir should be administered slowly over 1 hour to prevent precipitation in renal tubules.
To increase the efficacy of antiviral drugs various delivery approaches have been proposed, like encapsulation in poly(iso-butylcyanoacrylate) nanocapsules (Hillaireau er al. Int, J, Pharm. 2006, 324, 37-42. Particulate delivery systems could be able to promote sustained delivery of the antiviral drug. PLGA microparticles containing acyclovir for topical administration have been developed (de Jalon, 2001, 226, 181, 184) and acyclovir-loaded nanoparticles showed increased efficacy against herpex simplex virus type I in cell culture (de Jelon et al. Europ. J. Pharm. Biopharm. (2003) 56, 183-187). Semi-interpenetrating polymer network microspheres of acrylamide grafted on dextran or chitosan carrying up to 79% of acyclovir were prepared by emulsion-cross-linking method (Rokhade et al. Carbohydrate Polym. (2007) 605-607).
To enhance the oral bioavailability of acyclovir prodrugs have also been designed (Eur. J. Pharmac. Sci. 2004, 23, 319-325).
A poly(amidoamine) (PAA) copolymer with β-cyclodextrin can solubilise by complexation up to 11% w/w of the drug and the Acyclovir complex exhibits a higher antiviral activity than the free drug against herpes simplex virus type I in cell cultures (Bencini et al. J. Control. Release 2008, 126, 17-25).